Glutathione S-transferase M1 and T1 polymorphisms may predict adverse effects after therapy in children with medulloblastoma.
Glutathione S-transferases (GSTs) are polymorphic enzymes that catalyze the glutathione conjugation of alkylating agents, platinum compounds, and free radicals formed by radiation used to treat medulloblastoma. We hypothesized that GST polymorphisms may be responsible, in part, for individual differences in toxicity and responses in pediatric medulloblastoma. We investigated the relationship between GSTM1 and GSTT1 polymorphisms and survival and toxicity in 42 children with medulloblastoma diagnosed and treated at the Texas Children's Cancer Center. We conducted Kaplan-Meier analyses to determine if the GST polymorphisms were related to progression-free survival (PFS) and performed logistic regression to explore associations between GST polymorphisms and occurrence of grade 3 or greater (> or =Gr 3) myelosuppression, ototoxicity, nephrotoxicity, neurotoxicity, and intellectual impairment. Patients with at least one null genotype had a 4.3 (95% confidence interval, 1.1-16.8), 3.7 (1-13.6), and 6.4 (1.2-34) times increased risk for any > or =Gr 3 toxicity, any > or =Gr 3 toxicity excluding peripheral neuropathy, and any > or =Gr 3 toxicity requiring omission or cessation of chemotherapy, respectively. Compared with all others, patients with at least one null genotype had, on average, 27.2 (p x= 0.0002), 29 (p = 0.0004), and 21.7 (p = 0.002) lower full-scale, performance, and verbal intelligence quotient (IQ) scores, respectively. GSTM1 and GSTT1 polymorphisms may predict adverse events, including cognitive impairment after therapy, in patients with medulloblastoma. A larger study to validate these findings is under way.
Barahmani
Nadia
N
Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
Carpentieri
Sarah
S
Li
Xio-Nan
XN
Wang
Tao
T
Cao
Yumei
Y
Howe
Laura
L
Kilburn
Lindsay
L
Chintagumpala
Murali
M
Lau
Ching
C
Okcu
M Fatih
MF
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects*; D002528:Cerebellar Neoplasms / Q000188:drug therapy / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D003072:Cognition Disorders / Q000139:chemically induced / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D005982:Glutathione Transferase / Q000235:genetics*; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008527:Medulloblastoma / Q000188:drug therapy / Q000235:genetics*; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic
D005982:Glutathione Transferase; C413545:glutathione S-transferase T1